The long-term objective of this research is to control impulse conduction in specific nerve fibers selectively so that neural function may be altered to suit the clinical need for differential block; e.g. for surgery it is desirable to have transient block of pain and movement without disruption of autonomic function. Primary afferent nerve fibers are known to differ in their receptive fibers characteristics, which, in the traditional scheme for classifying fibers, have been linked to axon diameter. However, it is now established that diameter does not account for differences in susceptibility to anesthetics. Thus, this research is aimed at discovering and quantifying other differences between peripheral nerve fibers such as differences in "activity- dependence" (the magnitude and time course of changes in threshold or conduction velocity following impulse activity), and in membrane characteristics of trunk and CNS regions of sensory fibers. In vivo experiments will be conducted on fibers in anesthetized animals (rats) where function can be determined, but where pharmacological access to the fiber is restricted and where physiological stability is sometimes difficult to maintain. The mechanisms underlying the differences in functionally characterized fibers will therefore be studied under more controlled conditions in vitro on rat and frog nerves using voltage- clamped nodes and single conducting fibers. We plan to test immuno-markers as tags for axonal function which would permit the first physiological studies of functionally identified fibers in excised nerves in vitro. Techniques to exploit fiber differences by optimally combining factors known to modulate impulse conduction selectively (e.g. local anesthesia, pCO2, temperature) will be developed using in vitro experiments and computer models of impulse conduction. These sutdies will 1) continue to investigate the physiological basis of susceptibility to anesthetics; 2) study the relation to fiber function of other physiological and pharmacological properties, 3) study the response in the CNS to peripheral local anesthesia, where the neurophysiology of dorsal horn neurons will be examined with highly selective peripheral stimulation. Responses of dorsal horn neurons to peripheral input will be measured in vivo during peripheral application of local anesthetics to begin to understand the basis for perceptual changes that occur during the blockade of impulses in peripheral nerve.